ABSTRACT While delirium and dementia are the most common causes of cognitive impairment in older adults, their interrelationship is complex and poorly understood. Many questions remain unresolved: Does pre-existing Alzheimer's disease (AD) pathology increase vulnerability to delirium? Does delirium increase cognitive decline in those with AD pathology? Do AD pathology and delirium interact to promote cognitive decline or dementia? Project 1 will investigate the inter-relationship of delirium and long-term cognitive decline (LTCD) with molecular biomarkers of AD pathology according to 3 general components of the new ATN (Amyloid?? [A?], Tau, Neurodegeneration) descriptive classification scheme for AD biomarkers. We propose the following specific aims: (1) to examine the relationship between baseline cerebrospinal fluid (CSF) AD biomarkers (CSF A?42, total tau [t-tau], phospho-tau tau/A?42 ratios, and neurofilament light [NFL]), sampled prior to spinal anesthesia, and development of post-operative delirium and cognitive decline over 18-36 months in a new cohort of 400 older persons undergoing joint replacement surgery (SAGES II); (2) to evaluate associations of history of delirium and CSF AD biomarkers (sampled near 4 year follow-up) with LTCD (over a minimum of 8 years) in a probability sample from SAGES I (N=128): 64 patients who developed delirium during the initial hospitalization and 64 who did not develop delirium during the initial or subsequent hospitalizations; and (3) after correlating CSF and plasma levels of novel SiMoA assays of t-tau and NFL obtained at follow-up in the SAGES I probability sample (N=128), to examine the relationship of pre-operative levels of these markers obtained from stored plasma with delirium incidence/severity and LTCD following delirium. We have conducted detailed pilot work ensuring the feasibility of the proposed work, including assuring adequate numbers of available patients and their willingness to participate, and verifying feasibility and tolerability of all study procedures. We have demonstrated adequate statistical power to examine our aims. The success of the proposed work is further assured by a highly skilled interdisciplinary team of study investigators who have been working together for 2-11 years, by the demonstrated attainment of all of the previous aims, and by enrolling a large, complex cohort of over 560 surgical patients along with 119 non-surgical controls during the initial cycle. This project will probe whether fluid biomarkers identify patients who are more vulnerable to delirium, and are most likely to have cognitive decline following delirium. By probing the relationship of delirium and AD biomarkers, we will be well positioned to advance our mechanistic understanding and to develop more effective intervention strategies to forestall LTCD associated with delirium and AD. Moreover, this study may lay the groundwork for identification of potential plasma biomarkers for AD and related dementias (ADRD). If our hypotheses are confirmed, this study will offer compelling support for the importance of prevention of delirium to forestall the progression of cognitive decline in AD/ADRD.